Pseudogene-mediated DNA demethylation leads to oncogene activation.
Junsu Kwon, Yanjing V Liu, Chong Gao, Mahmoud A Bassal, Adrianna I Jones, Junyu Yang, Zhiyuan Chen, Ying Li, Henry Yang, Leilei Chen, Annalisa Di Ruscio, Yvonne Tay, Li Chai, Daniel G Tenen
Author Information
Junsu Kwon: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Yanjing V Liu: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Chong Gao: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. ORCID
Mahmoud A Bassal: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Adrianna I Jones: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115 USA. ORCID
Junyu Yang: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Zhiyuan Chen: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Ying Li: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Henry Yang: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Leilei Chen: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Annalisa Di Ruscio: Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA. ORCID
Yvonne Tay: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Li Chai: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. ORCID
Daniel G Tenen: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. ORCID
Pseudogenes, noncoding homologs of protein-coding genes, once considered nonfunctional evolutionary relics, have recently been linked to patient prognoses and cancer subtypes. Despite this potential clinical importance, only a handful of >12,000 pseudogenes in humans have been characterized in cancers to date. Here, we describe a previously unrecognized role for pseudogenes as potent epigenetic regulators that can demethylate and activate oncogenes. We focused on , a known oncogene in hepatocellular carcinoma (HCC) with eight pseudogenes. Using a locus-specific demethylating technology, we identified the critical CpG region for SALL4 expression. We demonstrated that pseudogene 5 hypomethylates this region through interaction with DNMT1, resulting in SALL4 up-regulation. Intriguingly, pseudogene 5 is significantly up-regulated in a hepatitis B virus model before SALL4 induction, and both are increased in patients with HBV-HCC. Our results suggest that pseudogene-mediated demethylation represents a novel mechanism of oncogene activation in cancer.
